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Drug Approval Process

Updated: Dec 13, 2021


Much of you are about to read is taken verbatim from the US Food and Drug Administration. The content of this blog has been abridged to reflect salient points in the drug development and clinical trial process. Please note that a drug discovery program requires, on average, expenditures well in excess of $1.0 – 2.0 billion by the sponsor, has a low probability of success and requires 10 -12 years of development. The patient-centric approach and the use of “omics” aims to cut that time and expenditure; however, the protocols and safety considerations will essentially be the priority.

Discovery, Development, Preclinical and Investigation New Drug Application

Typical drug or biologic approval begins with drug discovery, optimization and then a series of evaluations termed preclinical studies which evaluate the potential efficacy of the drug or biologic in vivo and in vitro as well as the drug or biologic’s pharmacological and toxicological profile among other important parameters.

Should the drug or biologic meet certain performance parameters within the sponsor’s guidelines, an Investigation New Drug (IND) application is filed with the Food and Drug Administration (FDA). The requirements for an IND are detailed under Title 21, Food and Drugs, Chapter I, Subchapter D, Part 312.

The FDA reviews the IND application and decides, applying current good manufacturing practice (CGMP) required under section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) in the manufacture of most investigational new drugs (IND) used in Phase 1 clinical trials. It is noteworthy that these drugs, which include biological drugs, are exempt from complying with 21 CFR part 211 under 21 CFR 210.2(c) (referred to as phase 1 investigational drugs). The FDA will also review proposed studies (protocols) during Phase I clinical evaluation.1

Researchers design clinical trials to answer specific research questions related to a medical product. These trials follow a specific study plan, called a protocol, that is developed by the researcher or manufacturer. Before a clinical trial begins, researchers review prior information about the drug to develop research questions and objectives. Then, they decide:

· Who qualifies to participate (selection criteria)

· How many people will be part of the study

· How long the study will last

· Whether there will be a control group and other ways to limit research bias

· How the drug will be given to patients and at what dosage

· What assessments will be conducted, when, and what data will be collected

· How the data will be reviewed and analyzed2

Phase 0, I, II, III, IV Clinical Programs

While discussed in a previous blog (l, I have provided a summary of the various clinical trials:

Phase 0

Phase 0 of a clinical trial is done with a small number of people, usually fewer than 15. Investigators use an exceedingly small dose of medication to make sure it isn't harmful to humans before they start using it in higher doses for later phases.

Phase 1a

In single ascending dose studies, small groups of subjects are given a single dose of the drug while they are observed and tested for a period of time to confirm safety. Typically, a small number of participants, usually three, are entered sequentially at a particular dose.

Phase 1

During Phase 1 studies, researchers generally test a new drug candidate in healthy volunteers. In most cases, 20 to 80 healthy volunteers participate in Phase 1. The primary purpose of a Phase 1 study is to evaluate the safety of a new drug candidate before it proceeds to further clinical studies.

Phase 2a

Phase 2a Clinical Trial means a Phase 2 Clinical Trial designed to generate initial data on short-term efficacy, safety, dosing and administration in patients who have the relevant disease or condition to be treated, diagnosed or prevented.

Phase 2

In Phase 2 studies, researchers administer the drug to a larger group of patients (typically up to a few hundred) with the disease or condition for which the drug is being developed to initially assess its effectiveness and to further study its safety.

Phase 3

Phase 3 trials compare a new drug to the standard-of-care drug. These trials assess the side effects of each drug and which drug works better. Phase 3 trials enroll 100 or more patients. Often, these trials are randomized. This means that patients are put into a treatment group, called trial arms, by chance.

Phase 4

A type of clinical trial that studies the side effects caused over time by a new treatment after it has been approved and is on the market.

Guidelines for the Manufactured Product

Because a Phase 1 clinical trial initially introduces an investigational new drug into human subjects, appropriate CGMP help ensure subject safety. Additionally, the FDA will review the pharmacological and toxicological results regarding the proposed drug as well as proposed dosing regimen.

During product development, the quality and safety of Phase 1 investigational drugs are maintained, in part, by having appropriate QC procedures in effect. Using established or standardized QC procedures and following appropriate CGMP will also facilitate the manufacture of equivalent or comparable IND product for future clinical trials as needed. Adherence to CGMP during manufacture of investigational drugs occurs mostly through:

· Well-defined, written procedures

· Adequately controlled equipment and manufacturing environment

· Accurately and consistently recorded data from manufacturing (including testing)

Manufacturers may have acceptable alternatives to meet the objectives described in this guidance. It is the manufacturer’s responsibility to provide and use such methods, facilities, and manufacturing controls to ensure that the phase 1 investigational drug meets appropriate standards of safety, identity, strength, quality, and purity. Manufacturers of investigational drugs should consider carefully how to best ensure the implementation of standards, practices, and procedures that conform to CGMP for their specific product and manufacturing operation.1

Guidelines for Clinical Trials

FDA Requirements for Clinical Trial Quality

· 21 CFR 312 broadly describes sponsor responsibilities for clinical trials

· Selection of qualified investigators

· Monitoring trial progress

· Ensuring the trial is conducted according to the investigational plan

· Review and analysis of accumulating evidence relating to product’s safety and effectiveness

· 21 CFR 314.126 broadly describes what constitutes an adequate and well-controlled study

· Study design permits a valid comparison with a control to provide a quantitative assessment of drug effect

· Method of selection of subjects provides adequate assurance that they have the disease or condition being studied

· Method of assigning patients to treatment and control groups minimizes bias and assures comparability of the groups

· Adequate measures are taken to minimize bias – Methods of assessment of subjects' response are well-defined and reliable

· Recommends a quality risk management approach to clinical trials

· Protocol be considered blueprint for quality Conduct of a risk assessment to identify and evaluate risks to critical study data and processes

· Monitoring is one aspect of the processes and procedures needed

· Monitoring plan be designed to address important and likely risks identified during risk assessment and discourages “One Size Fits All” approach to monitoring

Clinical Trials Transformation Initiative Recommendations:3

Create a culture that values and rewards critical thinking and open dialogue about quality, and that goes beyond sole reliance on tools and checklists. Focus effort on activities that are essential to the credibility of the study outcomes. Involve the broad range of stakeholders in protocol development and discussions around study quality. Prospectively identify and periodically review the critical to quality factors.


Keywords: Clinical Trials, FDA guidelines, Phase I, Phase II, Phase III, Phase IV


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